Methyldopa 500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Methyldopa 500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 565.00mg of methyldopa equivalent to 500mg anhydrous methyldopa
Excipient with known effect: Each tablet contains sunset yellow (E110)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film-coated tablet
Yellow biconvex film coated tablets with an approximate diameter of 12.5mm either plain or coded MYD 500 on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Clinical indications:
Methyldopa is indicated for hypertension
4.2 Posology and method of administration Posology
General considerations
Patients with renal impairment
Methyldopa is largely excreted by the kidney, and the patients with impaired renal function may respond to smaller doses.
Withdrawal of methyldopa is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.
Patients on treatment with other hypertensive agents
Therapy with methyldopa may be initiated in most patients already on treatment with other antihypertensive agents by terminating these antihypertensive medications gradually, as required. Following such previous antihypertensive therapy, methyldopa should be limited to an initial dose of not more than 500mg daily and increased as required at intervals of not less than two days.
When methyldopa is given to patients on other antihypertensive the dose of these agents may need to be adjusted to effect a smooth transition.
Addition of a thiazide
When 500mg of methyldopa is added to 50mg of hydrochlorothiazide, the two agents may be given together once daily.
Many patients experience sedation for two or three days when therapy with methyldopa is started or when the dose is increased. When increasing the dosage, therefore, it may be desirable to increase the evening dose first.
Adults
Initial dosage: Usually 250mg two or three times a day, for two days, increased at intervals of not less than two days by an additional 250-500mg daily until satisfactory control is achieved. This normally follows within 12-24 hours of reaching the effective dose for the individual patient, which is generally in the range of 5002000mg daily. It is seldom necessary to exceed 3g daily and, because methyldopa is largely excreted by the kidneys, patients with impaired renal function may respond to comparatively low doses.
Paediatric population
Initial dosage is based on 10mg/kg of body weight daily in 2-4 oral doses. The daily dosage then is increased or decreased until an adequate response is achieved. The maximum dosage is 65mg/kg or 3.0g daily whichever is less.
Older _ people
The initial dose in the elderly patients should be kept as low as possible, not exceeding 250mg daily; an appropriate starting dose in the elderly would be 125mg b.d. Increasing slowly as required, but not to exceed a maximum daily dosage of 2g. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
Method of administration
For oral administration
4.3 Contraindications
Methyldopa is contraindicated in patients with:
• hypersensitivity (including hepatic disorders associated with previous methyldopa therapy) to the active substance or to any of the excipients listed in section 6.1
• active hepatic disease, such as acute hepatitis and active cirrhosis
• depression
• on therapy with monoamine oxidase inhibitors (MAOIs).
Methyldopa is not recommended for the treatment of phaeochromocytoma (see section 4.4).
4.4 Special warnings and precautions for use
Haemolytic Anaemia
Acquired haemolytic anaemia has occurred rarely. Should symptoms suggest anaemia, haemoglobin and/or haematocrit determinations should be made. If anaemia is confirmed, tests should be done for haemolysis. If haemolytic anaemia is present, methyldopa should be discontinued. Stopping therapy with or without giving a corticosteroid, has usually brought prompt remission. Rarely however, deaths have occurred.
Positive direct Coombes test
Some patients on continued therapy with methyldopa develop a positive direct Coombs test. From the reports of different investigators, the incidence averages between 10% and 20%. A positive Coombs test rarely develops in the first six months of therapy, and if it has not developed within 12 months, it is unlikely to do so later on continuing therapy. Development of a positive Coombs test is also dose-related, the lowest incidence occurring in patients receiving 1g or less of methyldopa per day. The test becomes negative usually within weeks or months of stopping methyldopa.
Prior knowledge of a positive Coombs reaction will aid in evaluating a cross-match for transfusion. If a patient with a positive Coombs reaction shows an incompatible minor cross-match, an indirect Coombs test should be performed. If this is negative, transfusion with blood compatible in the major cross-match may be carried out. If positive, the advisability of transfusion should be determined by a haematologist.
Reversible Leucopenia
Reversible leucopenia, with primary effect on granulocytes has been reported rarely. The granulocyte count returned to normal on discontinuing therapy. Reversible thrombocytopenia has occurred rarely.
Hepatic function
Occasionally, fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in liver function tests. Jaundice, with or without fever, also may occur. Its onset is usually within the first two or three months of therapy. In some patients, the findings are consistent with those of cholestasis.
Rare cases of fatal hepatic necrosis have been reported. Liver biopsy, performed in several patients with liver dysfunction, showed a microscopic focal necrosis compatible with drug hypersensitivity. Liver function tests and a total and differential white blood cell count are advisable before therapy and at intervals during the first six weeks to twelve weeks of therapy, or whenever an unexplained fever occurs.
Should fever, abnormality in liver function, or jaundice occur, therapy should be withdrawn. If related to methyldopa, the temperature and abnormalities in liver function will then return to normal. Methyldopa should not be used again in these patients. Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.
Anaesthesia
Patients may require reduced doses of anaesthetic when on methyldopa. If hypertension does occur during anaesthesia, it can be usually controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.
Other information
Dialysis removes methyldopa; therefore, hypertension may recur after this procedure.
Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, therapy should be discontinued.
Methyldopa should be used in extreme caution in patients, or in near relatives of patients with hepatic porphyria.
Interference with laboratory tests:
Methyldopa may interfere with the measurement of urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and AST (SGOT) by the colorimetric method. Interference with spectrophotometric methods for AST (SGOT) analysis has not been reported.
As methyldopa fluoresces at the same wavelengths as catecholamines, spuriously high amounts of urinary catecholamines may be reported interfering with a diagnosis of phaeochromocytoma.
It is important to recognise this phenomenon before a patient with a possible phaeochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid) by those methods, which convert VMA to vanillin.
Rarely, when urine is exposed to air after voiding, it may darken because of the breakdown of methyldopa or its metabolites.
Excipients:
Methyldopa contain the colouring agent Sunset yellow (E110). This may cause an allergic reaction in some individuals.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol: concomitant use may enhance the hypotensive effect.
Alprostadil: concomitant use may enhance the hypotensive effect.
Anaesthetics: as concomitant use may enhance the hypotensive effect, patients may require reduced doses of anaesthetics when on methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors.
Analgesics: NSAIDs antagonise the hypotensive effect.
Antibacterials: concomitant use with linezolid should be avoided as the hypotensive effect may be enhanced.
Antipsychotics: concomitant use can increase the risk of extrapyrimidal effects and enhance the hypotensive effect.
Anxiolytics and hypnotics: concomitant use may enhance the hypotensive effect. Beta-blockers: concomitant use may enhance the hypotensive effect. Calcium-channel blockers: concomitant use may enhance the hypotensive effect. Corticosteroids: concomitant use may antagonise the hypotensive effect.
Diuretics: concomitant use may enhance the hypotensive effect.
Dopaminergics: concomitant use may antagonise the antiparkinsonian effect of this type of medicine. Concomitant use with levodopa or entacapone may enhance the hypotensive effect.
Lithium: When methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity. Neurotoxicity may occur without increased plasma-lithium concentration.
Moxisylyte: concomitant use may enhance the hypotensive effect.
Muscle relaxants: concomitant use with baclofen and tizanidine may enhance the hypotensive effect.
Nitrates: concomitant use may enhance the hypotensive effect.
Oestrogens andprogestogens: oestrogens and combined oral contraceptives antagonise the hypotensive effect.
Beta2 sympathomimetics: acute hypotension has been reported with salbutamol infusion.
Ulcer-healing drugs: carbenoxolone antagonises the hypotensive effect.
Other antihypertensives: When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive action may occur. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy.
Other classes of drugs:
The anti-hypertensive effect of Methyldopa may be diminished by sympathomimetics, phenothiazines, tricyclic anti-depressants and MAOIs (see section 4.3) In addition, phenothiazines may have addictive hypotensive effects.
Iron: concomitant use may reduce the hypotensive effect. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulphate, or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa.
4.6 Fertility, pregnancy and lactation
Pregnancy
Methyldopa has been used under close medical supervision for the treatment of hypertension during pregnancy. There was no clinical evidence that methyldopa caused foetal abnormalities or affected the neonate but it has been in wide use for many years without apparent ill consequence, animal studies having shown no hazard. If drug therapy is needed in pregnancy, this drug can be used if there is no safer alternative.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used in pregnancy the possibility of foetal harm appears remote.
Breast-feeding
Methyldopa crosses the placental barrier and appears in cord blood and breast milk.
Although no obvious teratogenic effects have been reported, the possibility of foetal injury cannot be excluded and the use of the drug in women who are or may become pregnant or who are nursing their new-born infants requires that anticipated benefits be weighed against possible risks.
4.7 Effects on ability to drive and use machines
Methyldopa can cause sedation , usually transient during the initial period of therapy or whenever the dose is increased. If affected patients should not carry out activities where alertness is necessary such as driving a car or operating machinery.
4.8 Undesirable effects
The following reactions have been reported:
The most common side-effect of methyldopa is drowsiness. This is usually transient and may occur during the initial period of therapy or when the dose is increased.
Infections and infestations: Sialadenitis.
Blood and lymphatic system disorders: Haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia.
Endocrine disorders: Hyperprolactinaemia.
Psychiatric disorders: Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido.
Nervous system disorders: Sedation (usually transient), headache, paraesthesia, Parkinsonism, Bell's palsy, involuntary choreoathetotic movements. Impaired mental acuity, prolonged carotid sinus hypersensitivity. Dizziness, light headedness, and symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure).
Cardiac disorders: Bradycardia, aggravation of angina pectoris, myocarditis, pericarditis.
Vascular disorders: Orthostatic hypotension (decrease daily dosage).
Respiratory, thoracic and mediastinal disorders: Nasal stuffiness.
Gastrointestinal disorders: Nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, sore or 'black' tongue, pancreatitis.
Hepatobiliary disorders: Liver disorders including hepatitis, jaundice.
Skin and subcutaneous tissue disorders: Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Lupus like syndrome, mild arthralgia with or without joint swelling, myalgia.
Reproductive system and breast disorders: Breast enlargement, gynaecomastia, amenorrhoea, lactation, impotence, failure of ejaculation.
General disorders and administrative site conditions: Asthenia or weakness, oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs of heart failure appear.), drug-related fever.
Investigations: Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, rise in blood urea.
Reporting of suspected adverse reactions
Reporting suspected adverse drug reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
Acute over dosage may produce acute hypotension with other responses attributable to brain and gastro-intestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distension, flatus, diarrhoea, nausea, and vomiting).
Management
If ingestion is recent, emesis may be induced or gastric lavage performed. There is no specific antidote. Methyldopa is dialyzable. Treatment is symptomatic. Infusions may be helpful to promote urinary excretion and pressor agents given cautiously. Special attention should be directed towards cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity. Administration of sympathomimetic agents may be indicated. When chronic over dosage is suspected, methyldopa should be discontinued.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiadrenergic Agent ATC code: C02AB
Methyldopa is an antihypertensive agent, which may act centrally by stimulating alpha-adrenergic receptors. It inhibits the decarboxylation of dopa to dopamine, but this action does not appear to be responsible for its hypotensive effect. The antihypertensive effect of methyldopa is probably due to its metabolism to alpha-methylnoradrenaline, which lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activityMethyldopa reduces the tissue concentrations of dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine) and serotonin.
5.2 Pharmacokinetic properties
Methyldopa is incompletely absorbed from the gastro-intestinal tract. Bioavailability after oral administration averages 25%. Peak plasma levels were reached about two hours after oral ingestion. Plasma protein binding is reported to be minimal. It crosses the placenta and small amounts appear in breast milk.
The plasma half-life of methyldopa is 105 minutes. It is partly conjugated, mainly to the o-sulphate, and is excreted by the kidneys. Elimination follows a biphasic pattern regardless of the route of administration. Renal excretion accounts for about two thirds of drug clearance from plasma.
5.3 Preclinical safety data
No relevant information.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline Cellulose
Starch
Povidone
Magnesium Stearate Sodium Starch Glycollate Methanol Coating:
Methanol
Methylene Chloride Methocel E15 Premium Ethocel 10 CPS Diethyl Phthalate
Opaspray K-1F-6035 Yellcontaining:
Titanium Dioxide (E171)
Quinoline Yellow Aluminium Lake (E104)
Sunset Yellow FCF Aluminium Lake FD&C Yellow No. 6 (E110)
Indigo Carmine Aluminium Lake FD&C Blue No. 2 (E132)
Opaspray K-1-17000 (White) containing:
Titanium Dioxide (E171)
6.2 Incompatibilities
None
Shelf life
6.3
3 years
6.4 Special precautions for storage
Store in a cool dry place. Store in the original package in order to protect from light
6.5 Nature and contents of container
Polypropylene tubular container equipped with an open end to accept a polyethylene closure with a tamper-evident tear strip containing 50, 56, 100, 250, 500 or 1000
Not all packs sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St Neots
Cambridgeshire
PE19 8ET
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0361
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 17/03/2006 Date of latest renewal: 02/04/2009
10
DATE OF REVISION OF THE TEXT
13/10/2015